Selective Anticancer Effects of a P-I Metalloproteinase from Bothrops Moojeni Snake Venom (BthMP) on Lung Cancer Cells

Background: Lung cancer remains a leading cause of mortality, mainly due to aggressive metastasis and therapeutic resistance. Snake venom metalloproteinases (svMPs), particularly the P-I class, are promising sources for novel antitumor agents. Objectives: This study investigated the impacts of BthMP, a P-I svMPs from Bothrops moojeni venom, on human lung carcinoma (A549) cells in comparison to non-cancerous human bronchial epithelial cells (BEAS-2B). Methods and Results: BthMP demonstrated potent and selective anti-cancer activity. It significantly inhibited key metastatic processes in A549 cells, including adhesion, migration, and invasion, while suppressing long-term proliferation, as shown by reduced colony formation and increased lactate dehydrogenase (LDH) release. Mechanistically, BthMP induced a massive increase in intracellular reactive oxygen species (ROS) by over 2000% and elevated nitric oxide (NO) by 35% in A549 cells, driving a state of lethal oxidative stress. Crucially, these cytotoxic and anti-metastatic effects were minimal in BEAS-2B cells; BthMP even suppressed basal ROS and NO levels in this non-cancerous line. The anti-migratory effects of BthMP were completely dependent on its zinc-based catalytic activity, as they were abolished by pretreatment with ethylenediaminetetraacetic acid. By simultaneously disrupting cell–matrix interactions and inducing selective, catastrophic oxidative stress in cancer cells, BthMP presents a dual-pronged anti-metastatic mechanism. Conclusions: These findings establish BthMP as a promising therapeutic scaffold for developing novel treatments against lung cancer progression.